Structural and mechanistic insights into the cleavage of clustered O-glycan patches-containing glycoproteins by mucinases of the human gut.

Autor: Taleb V; Institute of Biocomputation and Physics of Complex Systems, University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain., Liao Q; Departament de Química Inorgánica i Orgánica (Secció de Química Orgánica) and Institut de Química Teorica i Computacional (IQTCUB), Universitat de Barcelona, 08028, Barcelona, Spain., Narimatsu Y; Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark., García-García A; Institute of Biocomputation and Physics of Complex Systems, University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain., Compañón I; Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química, E-26006, Logroño, Spain., Borges RJ; Departamento de Biofísica e Farmacologia, Instituto de Biociências, Universidade Estadual Paulista (UNESP), Botucatu, Brazil., González-Ramírez AM; Institute of Biocomputation and Physics of Complex Systems, University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain., Corzana F; Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química, E-26006, Logroño, Spain., Clausen H; Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark., Rovira C; Departament de Química Inorgánica i Orgánica (Secció de Química Orgánica) and Institut de Química Teorica i Computacional (IQTCUB), Universitat de Barcelona, 08028, Barcelona, Spain. c.rovira@ub.edu.; Institució Catalana de Recerca i Estudis Avancats (ICREA), 08010, Barcelona, Spain. c.rovira@ub.edu., Hurtado-Guerrero R; Institute of Biocomputation and Physics of Complex Systems, University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain. rhurtado@bifi.es.; Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark. rhurtado@bifi.es.; Fundación ARAID, 50018, Zaragoza, Spain. rhurtado@bifi.es.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jul 26; Vol. 13 (1), pp. 4324. Date of Electronic Publication: 2022 Jul 26.
DOI: 10.1038/s41467-022-32021-9
Abstrakt: Mucinases of human gut bacteria cleave peptide bonds in mucins strictly depending on the presence of neighboring O-glycans. The Akkermansia muciniphila AM0627 mucinase cleaves specifically in between contiguous (bis) O-glycans of defined truncated structures, suggesting that this enzyme may recognize clustered O-glycan patches. Here, we report the structure and molecular mechanism of AM0627 in complex with a glycopeptide containing a bis-T (Galβ1-3GalNAcα1-O-Ser/Thr) O-glycan, revealing that AM0627 recognizes both the sugar moieties and the peptide sequence. AM0627 exhibits preference for bis-T over bis-Tn (GalNAcα1-O-Ser/Thr) O-glycopeptide substrates, with the first GalNAc residue being essential for cleavage. AM0627 follows a mechanism relying on a nucleophilic water molecule and a catalytic base Glu residue. Structural comparison among mucinases identifies a conserved Tyr engaged in sugar-π interactions in both AM0627 and the Bacteroides thetaiotaomicron BT4244 mucinase as responsible for the common activity of these two mucinases with bis-T/Tn substrates. Our work illustrates how mucinases through tremendous flexibility adapt to the diversity in distribution and patterns of O-glycans on mucins.
(© 2022. The Author(s).)
Databáze: MEDLINE
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